Obesity has emerged as one of the most serious health problems worldwide, and according to the WHO there are currently ~1.5 billion overweight and ~500 million obese adults. The situation in the United States is even worse, with ~60% of US adults either obese or overweight. Obesity is associated with a number of diseases such as hypertension, diabetes, heart disease, nonalcoholic fatty liver disease, and various cancers such as liver, colon, breast, gastric, gall bladder, endometrial, esophagus, pancreas and renal cell carcinoma. Obesity is identified as a contributing factor to ~200,000-400,000 deaths per year in the US alone. According to current estimates the US is spending ~$150 billion on obesity and its related health costs. Therefore, it is extremely urgent to identify effective strategies to cure obesity since it is associated with a number of life threatening and medically expensive diseases. The primary goal in the treatment of obesity is to remove excess fat deposits in the body. The aim of this application is to create models that mimic human obesity and investigate approaches that effectively treat obesity in mice. Consequently, these approaches can be tested in pre-clinical and clinical settings to treat obese patients. I propose to investigate two specific approaches based on direct targeting and depletion of fat deposits in white adipose tissue (WAT), and two specific approaches based on energy expenditure ability of brown adipose tissue (BAT). Approach 1: By utilizing the powerful lipolysis-inducing function of the tumor secretory factor zinc-?2-glycoprotein (ZAG), I propose that transient induction of ZAG in the WAT of obese mice could function as a powerful strategy to induce lipolysis, reduce body fat and treat obesity. Approach 2: To create a drug-free, cost-effective and long-term strategy, I propose to investigate an approach where implantation of macroencapsulated preadipocytes that secrete ZAG could be a powerful cell therapy approach to treat obesity. Approach 3: Based on very interesting recent observations that early B cell factor-2 (Ebf2) determines brown versus white adipocyte differentiation and reprograms white preadipocytes into brown adipocytes, I propose that, in the obese condition, transient expression of Ebf2 in the preadipocytes of WAT and inducing them to differentiate into brown adipocytes could be a very effective BAT-mediated energy expenditure strategy for the treatment of obesity. Approach 4: PGC1? is the master regulator of BAT- mediated thermogenesis and controls the entire thermogenesis program. Therefore, I propose that implantation of macroencapsuled PGC1?-overexpressing brown adipocytes increases thermogenesis, reduces body fat by dissipating energy as heat and effectively treats obesity. The proposed approaches to treat obesity have direct clinical relevance and, if successful, will lead to a series of pre-clinical studies. Ultimately, similar approaches can be implemented to treat obese patients. The macroencapsulated cell implantation approaches especially, will be very cost-effective for continuous, long-term treatment of morbidly obese patients.